Certain 2-amino-3,4-dihydrogen-inazolin-4-ones and 4-thiones

ABSTRACT

Substituted 2-amino-3,4-dihydroquinazoline-4-one and substituted 2-amino-4-(3H)-quinazolinethionone and their utility as antihypertensive agents.

United States Patent [72] Inventors l-lans-Jurgeu E. Hess;

Gerald F. Holland, both of Groton, Conn. [21] Appl. No. 7,347 [22] FiledJan. 28, 1970 [45] Patented Sept. 28, l97l [73] Assignee Pfizer Inc.

New York, N.Y. Continuation of application Ser. No. 576,549, Sept. 1,1966, now abandoned which is a continuation-in-part of application Ser.No. 442,205, Mar. 23, 1965, now abandoned.

[54] CERTAIN 2-AMINO-3,4-DIHYDROGEN- lNAZOLlN-4-ONES AND 4-THIONES 17Claims, No Drawings [52] US. Cl 260/2565 R,

260/256.4 Q, 424/200, 424/251 [51] lnt.Cl C07d 51/48 50 Field 61 Search260 2564 Q, 256.5 R

[56] References Cited UNITED STATES PATENTS 3,257,400 6 1966 Wagner260/256.4 (0) 3,274,194 9 1966 l-layao 260 2564 (Q) 3,301,855 1 1967Blatter 260/256.4 (Q) 3,322,756 5 1967 Ruschig 6161. 260 2564 (O) OTHERREFERENCES Grout et aL, J. Chem. Soc., 1960, pp. 3540- 3545. Postorskiiet al., Zhur. Obscheikhim, vol. 32 (1962), pp. 3323- 3331.

Primary Examiner-Alex Mazel Assistant Examiner-R. J. GallagherAttorneyConnolly and Hutz ABSTRACT: Substituted2-amino-3,4-dihydroquinazoline-4- one and substituted2-amino-4-(3H)-quinazolinethionone and their utility as antihypertensiveagents.

CERTAIN 2-AMINO-3,4-DIHYDROGEN-INAZOLIN-4- ONES AND 4-THIONES This is acontinuation of application Ser. No. 576,549, filed Sept. 1, 1966, whichapplication is in turn a continuation-inpart of application Ser. No.442,205, filed Mar. 23, 1965, both of which are now abandoned.

This invention relates to certain novel organic nitrogen compounds. Moreparticularly, it is concerned with various new and useful organicnitrogen heterocycles having an amphoteric character and with the saltswhich such compounds form with pharmacologically acceptable acids andbases.

The amphoteric compounds which are included within the purview of thisinvention are selected from the group consisting of those ofthe formula:

wherein R is selected from the group consisting of methoxy, ethoxy andmethyl; R is a member selected from the group consisting ofN,N-dimethylamino, N,N-diethylamino, N,N-diallylamino, N-homopiperidino,N,N-di(B-hydroxethyl) N- ethyl-N-allylamino, N,N-methylpiperazino,N,N-(npropyl)piperazino, N,N'-allylpiperazino, N- monoisopropylamino,N-mono(B-hydroxyethyl)amino and N ,N'-2-furoylpiperazino; X is selectedfrom the group consisting of oxygen and sulfur;

and,

2-(N,N-dimethylamine)-7-methoxy-3,4-dihydroquinazoline-4-one2-(N,N-diethylamino)-7-methoxy-3,4-dihydroquinazoline- 4-one2-(N,N-dimethylamino)-7-methoxy-4-(3H)-quinazolinethione2-(N,N-diethylamino)-7-methoxy-4-(3H)-quinazolinethione and the saltsthereof with and bases,

Typical of the specific members of the 2-amino-3,4-dihydroquinazolines-4-one series are such compounds as 2-(N,N-dimethylamino)-6,7-dimethoxy-3,4-dihydroquinazoline-4-one,2-(N,N-diethylamino)-6,7-dimethoxy-3,4- dihydroquinazoline-4-one,2[N-(N'-methylpiperazino)]-6,7- dimethoxy-3,4-dihydroquinazoline-4-oneand the like. Specific examples of the 2-amino-4(3H)-quinazolinethioneseries include: 2-(N,N-diethylamino)-6,7-dimethoxy-4-(3H)-quinazolinethione, 2-(N,N-dimethylamino)-6,7-dimethoxy-4 (3H)-quinazolinethione, 2(N,N-diallylamino)-6,7-dimethoxy-4(3l-I)-quinazolinethione, and 2-[N-(N-methylpiperazino)]-6,7-dimethoxy-4(3H)-quinazolinethione. These particular compounds areall highly potent in their antihypertensive effects and they afford along duration of action as well.

pharmacologically-acceptable acids The process employed for preparingthe novel 2-amino-3,4- dihydroquinazoline-4-one compounds of thisinvention involves treating the corresponding2-halo-3,4-dihydroquinazoline-4-ones with the appropriate amine base,viz, RH where R is as previously defined. In general, it is onlynecessary that at least an equimolar amount of amine base be employed,but in practice one ordinarily uses an excess of same as this serves toshift the reaction to completion, In addition, the excess amine can alsofunction as a solvent for the reaction. A preferred excess for thesepurposes would be from about 2 to about moles of amine to 1 mole of the2-halo- 3,4-dihydroquina zoline-4-one; If a reaction-inert solvent isemployed for the reaction, one would ordinarily use a polar organicsolvent such as a lower alkanol like methanol, ethanol and isopropanol,etc., or an aromatic hydrocarbon solvent such as benzene, toluene,xylene, and so forth. The temperature at which this reaction can beconducted varies within the range of from between about 50 C. up toabout 200 C. for a period of from about 1 to 12 hours. A preferredreaction temperature and time for this reaction would be about -150" C.for about 2-4 hours. ln the case where a solvent was used or when theboiling point of the amine was below the desired reaction temperature, apressure bottle was ordinarily employed as the proper reaction vessel.Upon completion of the reaction, the product is recovered byconventional methods. For instance, evaporation of the reaction mixtureto dryness affords a crude solid residual material, which can then beeither triturated with water or precipitated from dilute aqueous acid incrystalline form and subsequently recrystallized from any number ofappropriate organic solvents, including the N,N-dialkyl loweralkanoamides like dimethylformamide and dimethylacetamide or the loweralkanols such as ethanol and isopropanol.

The starting materials necessary for the reaction procedure of thisinvention, viz, the 2-halo-3,4-dihydroquinazoline-4- ones andpreferably, the 2-chlor0 and 2-bromo compounds, are obtained by treatingthe corresponding 2,4-dihaloquinazolines with a strong base compoundsuch as an alkali metal hydroxide in an aqueous reaction medium whichmay also contain an organic solvent as well. A molar excess of base isgenerally employed, while preferred organic solvents for these purposesinclude water-miscible inert polar organic solvents liketetrahydrofuran, dioxane and the N,N-dialkyl lower alkanoamides, such asdimethylacetamide and dimethylformamide, etc. The2,4-dihaloquinazolines, on the other hand, are all obtained by usingessentially known methods. For instance,2,4-dichloro-6,7-dimethoxyquinazoline has been prepared according to theprocedure described by F. H. S. Curd et al. in the Journal of theChemical Society (London), 1948, p. 1759. This procedure is equallyapplicable to the other starting 2,4- dihaloquinazolines as well, i.e.,as regards their method of preparation.

The 2-amino-3,4-dihydroquinazoline-4-ones in addition to being valuableantihypertensives per se, advantageously serve as useful startingmaterials in the preparation of the herein disclosed2-amino-4(3H)-quinazolinethiones. This conversion is a two step sequencewhich proceeds through an intermediate 4-chloro derivative.Schematically, the reaction sequence is as follows:

/ W WW [w M e l l O1 S I II III The 2-amino-3,4-dihydroquinazoline-4-one(l) as the hydrochloride salt is mixed with an excess (molewise) ofphosphorus oxychloride and the resulting mixture is refluxed for aperiod of from one-half to 24 hours and then evaporated almost todryness. The material which crystallizes on standing is thehydrochloride salt of the corresponding 2-amino-4- chloroquinazoline.Thisintermediate is converted to its free base and isolated bydissolving it in aqu eo.us sodium bicarbanate and extracting withaniorganic solventrwhich is immisciblewith water, for example,chloroform, separating the organic phase. and evaporating to dryness.The residue product crystallizes on standing.

The second and final step consists of dissolving the intermediate4-chloro derivative in tetrahydrofuran, adding thereto a slight excessof a sodium hydrogen sulfide aqueous solution followed by the additionof a catalytic amount of IN HCl. If the chloro derivative is utilized inthe form of an acid addition salt, no HCl is necessary. The resultingsolution is stirred for about 1-3 hours, evaporated, and triturated withhot chloroform. Isolation by evaporation and recrystallization frommethanol affords the desired 2-arnino-4(3H)-quinazolinethione in goodyields.

inasmuch as the 2-amino-3,4-dihydroquinazoline4-ones and2-amino-4(3H)-quinazolinethiones of this invention are amphotericcompounds, they are capable of forming a wide variety of salts withvarious acids and bases, and particularly with the strong acids andbases in view of the nature of the compounds undergoing such a reaction.Some of these salts are pharmaceutically acceptable to begin with,whereas others must first be converted back to the free amphotericcompound and then subsequently converted to the desired salt which isfit for oral human consumption. This is done by simply treating theamphoteric compound with at least a substantially equimolar amount ofthe chosen acid or base in an aqueous solution or in an organic solventsuch as methanol or ethanol. The solid salt is then obtained uponevaporation of the solvent, and this usually occurs in the form of acrystalline residue.

Among the various acids which can be used to prepare thepharmaceutically acceptable acid addition salts of this invention in themanner just described are those which contain pharmacologicallyacceptable anions such as, for example, hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, lacticacid, citric acid, tartaric acid, oxalic acid, benzoic acid, succinicacid, maleic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid and p-toluenesulfonic acid and so on. The baseswhich can be used include those which form nontoxic salts with thesecompounds in view of their possession of a pharmacologically acceptablecation. As a result, such bases will generally include the alkali metaland alkaline-earth metal hydroxides like sodium, potassium, calcium andmagnesium hydroxide, for example.

As previously indicated, the compounds of the present invention are allreadily adapted to therapeutic use as antihypertensive agents in view oftheir ability to lower the blood pressure of the correspondinglyagitated subjects. For example, 2- (N,N-diethylamino)-6,7-dimethoxy-3,4-dihydroquinazoline- 4-one and2-(N,N-diethylarnino)-6,7-dimethoxy-4(3H)-quinazolinethione have beenfound to produce a definite antihypertensive response in lowering theblood pressure of hypertensive rats and dogs to a statisticallysignificant degree when orally administered to them. Additionally, theseparticular compounds accomplish this result without causing any unwantedside effects to occur in the subject being so treated. As a matter offact, no problems of toxicity or any other untoward side effects haveever been encountered with the compounds of this invention when they areadministered either orally or parenterally to hypertensive subject.

In accordance with a method of treatment of the present invention, theherein described antihypertensives can be administered to an agitatedsubject via the oral or parenteral routes. In general, these compoundsare most desirably administered in doses ranging from about mg. up to900 mg. per day, although variations will necessarily occur dependingupon the weight of the subject being treated and the particular route ofadministration chosen. However, a dosage level, that is, in the rangeoffrom about 0.15 mg. to about mg. per kg. of body weight per day ismost desirably employed in order to achieve effective results.Nevertheless, it is to be appreciated that still other variations mayalso occur in this respect, depending upon the species of animal beingtreated and its individual response to said medicament, as well as onthe particular type of pharmaceutical formulation chosen and the timeperiod and interval at which such administration is carried out. In someinstances, dosage levels below the lower limit of the aforesaid rangemay be more than adequate, while in other cases still larger dosages maybe employed without causing any harmful or deleterious side effects tooccur provided that such higher dose levels are first divided intoseveral smaller doses that are to be administered throughout the day.

In connection with the use of the compounds of this invention for thetreatment of agitated subjects, it is to be noted that they may beadministered either alone or in combination with pharmaceuticallyacceptable carriers by either of the routes previously indicated, andthat such administration can be carried out in both single and multipledosages. More particularly, the novel compounds of this invention can bead ministered in a wide variety of different dosage forms, i.e., theymay be combined with various pharmaceutically accepta ble inert carriersin the form of tablets, capsules, lozenges, troches, hard candies,powders, sprays, aqueous suspensions, injectable solutions, elixirs,syrups, and the like. Such carriers include solid diluents or fillers,sterile aqueous media and various nontoxic organic solvents, etc.Moreover, such oral pharmaceutical compositions can be suitablysweetened and/or flavored by means of various agents of the typecommonly employed forjust such a purpose. In general, thetherapeuticallyeffective compounds of this invention are present in suchdosage forms at concentration level ranging from about 0.5 percent toabout percent by weight of the total composition, i.e., in amounts whichare sufficient to provide the desired unit dosage previously indicated.

For purposes of oral administration, tablets containing variousexpedients such as sodium citrate, calcium carbonate and dicalciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tableting purposes. Solid compositions ofa similar type may also be employed as fillers in soft and hardfilledgelatin capsules; preferred materials in this connection would alsoinclude lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the essential active ingredient may becombined with various sweetening or flavoring agents, coloring matter ordyes and, if so desired, emulsifying and/or suspending agents, togetherwith such diluents as water, ethanol, propylene glycol, glycerin andvarious like combinations thereof.

For purposes of parenteral administration, solutions of these particularcompounds in sesame or peanut oil or in aqueous-propylene glycol or inN,N-dimethylformamide may be employed, as well as sterile aqueoussolutions of the corresponding water-soluble, nontoxic salts previouslyenumerated. Such aqueous solutions should be suitably buffered ifnecessary and the liquid diluent first rendered isotonic with sufficientsaline or glucose. These particular aqueous solutions are especiallysuitable for intravenous, intramuscular and intraperitoneal injectionpurposes. In this connection, the sterile aqueous media employed arereadily obtained by standard techniques well known to those in the art.For instance, distilled water is ordinarily used as the liquid diluentand the final preparation is passed through a suitable bacterial filter,such as a sintered-glass or a diatomaceous-earth or unglazed porcelainfilter. Preferred filters of this type include the Berkefeld, theChamberland, and the asbestos disc-metal Seitz filter, wherein the fluidis sucked through the filter candle into a sterile container with theaid of a suction pump. Needless to say, the necessary steps should betaken throughout the preparation of these injectable solutions to ensurethat the final products are obtained in a sterile condition.

This invention is further illustrated by the following examples, whichare not to be construed in any way or manner as imposing limitationsupon the scope thereof. On the contrary, it is to be clearly understoodthat resort may be had to various other embodiments, modifications andequivalents thereof EXAMPLE 12-Chloro-6,7-Pimethoxy-3.4-DihydroquinazolineA-one A mixture wasprepared consisting essentially of 129 g. of2,4-dich1oro-6,7-dimethoxyquinazoline [prepared according to the methodof F. H. S. Curd et al., J. Chem. $00., p. 1759 (1948)]suspended in 3liters of 1N aqueous sodium hydroxide and one liter of tetrahydrofuran.This mixture was stirred for approximately 2% hours at room temperaturebefore complete solution occurred. Subsequent acidification with glacialacetic acid then afforded a crystalline precipitate. which was filteredand washed with successive portions of water, benzene and methanol.After drying to constant weight, there was obtained 115 g. (97%) ofdesired product, viz, 2-chloro-6,7-dimethoxy-3,4-dihydroquinazoline-4-one melting at 267-270 C.(decomp.).

Anal. Calcd. for C l-bN O Clz C, 49.90; H, 3.80; N, 11.64;

C1, 14.73. Found: C, 49.99; H, 3.98;N,11.56;Cl,14.43.

EXAMPLE 11 The procedure described in Example 1 is repeated to preparevarious other 2-ha1o-3,4-dihydroquinazoline-4-ones of the followingformula (where Y is halogen), starting from the appropriate2,4-dihaloquinazoline compounds:

Similarly, when R and R taken together are benzo, the procedure ofExample 1 is followed to prepare the corresponding compounds startingfrom the appropriate 2,4-dihaloquinazoline compounds:

Y=Cl or Br Example 1112-(N,N-Diethylamino)-6.7-Dimethoxy-3,4-Dihydroquinazoline-4-one Amixture of 4.8 g. (0.03 mole) of 2-chloro-6,7-dimethoxy-3,4-dihydroquinazoline-4-one and m1. of diethylamine (7.1 g., 0.0973mole) in 50 ml. of ethanol was placed in a pressure bottle and shaken at130 C. for 3 hours. The reaction mixture was then cooled to roomtemperature, the solvent removed by means of evaporation under reducedpressure and the residual material triturated with water. The solidproduct so obtained was then collected by means of suction filtrationand recrystaL lized once from ethyl alcohol to afford a 70% yield of2-(N,N- diethylamino)-6,7-dimethoxy-3,4-dihydroquinazoline-4-one,m.p.215-217C.

Anal. Calcd. for c,,H,,N,o,= C, 60.63; H, 6.91; N, 15.15.

Found: C, 60.39; H, 6.67; N, 15.36.

EXAMPLE 1V EXAMPLE V2-(N,N-Dial1y1amino)-6,7-Dimethoxy-3,4-Dihydroquinazoline-4-one Theprocedure described in example 111 was followed except that diallylamine(9.7 g., 0.10 mole) was the organic base employed instead ofdiethylamine. In this particular case, the product obtained was2-(N,N-diallylamino)-6,7-dimethoxy- 3,4-dihydroquinazoline-4-one, m.p.ll9lC.

Anal. Calcd. for C ll N O C, 63.77; H, 6.36; N, 13.95.

Found: C, 63.58; H, 6.10; N, 13.77.

EXAMPLE V1 2-[N-(N-Methylpiperazino)]-6,7 Dimethoxy-3,4-Dihydroquinazoline-4-one The procedure described in example 111 wasfollowed except that N-methylpiperazine (10 g., 0.10 mole) was theorganic base employed instead of diethylamineiln this particular case,the product obtained was 2-[N-(N-40 -methylpiperazino)]-6,7-dimethoxy-3,4-dihydroquinazoline-4-one, m.p. 250-252 C Anal. Calcd.for C,,,H N O C, 59.19; H, 6.62; N, 18.41.

Found: C, 59.47; H, 6.60; N, 18.29.

EXAMPLE V11 2-( N-Homopiperidino)-6,7-Dimethoxy-3,4-Dihydroquinazoline-4-one The procedure described inexample 111 was followed except that Nhomopiperidine (0.10 mole) was theorganic base employed instead of diethylamine. The product is obtainedin good yields, m.p. 253-255 C.

EXAMPLE VlIl 2-).N(N'-n-propylpiperazino)]-6,7-Dimethoxy-3,4-Dihydroquinazoline-4-one The procedure described in example 111 wasfollowed except that N-n-propylpiperazine (0.10 mole) was the organicbase employed instead of diethylamine. The product is obtained in goodyields, m.p. 223225 C.

EXAMPLE 1X 2-[N-(N'-Allylpiperazino)]-6,7-Dimethoxy-3,4-Dihydroquinazoline-4-one The procedure described in example 111 wasfollowed except that N-allylpiperazine (0.10 mole) was the organic baseemployed instead of diethylamine. The product is obtained in goodyields, m.p. 219-200 C.

EXAMPLE lXA 2-[N-(N'-2-Furoylpiperazino) ]-6,7-Dimethoxy-3,4-Dihydroquinazolinet-one The procedure described in example III wasfollowed except that N-2-furoylpiperazine (0.10 mole) was the organicbase employed instead of diethylamine. The product is obtained in goodyields, m.p. 283-286 C.

EXAMPLE X The procedure of example III is again employed to prepare thefollowing compounds, which are listed below in the table of thisexample, starting from the appropriate 2-halo-3,4-dihydroquinazoline-t-one (of examples l-ll) and the correspondingamines:

N Rr- R R NH R1 R2 R CHaO CHaO N(CH2CH2OH)2 CHQO OHQO N(C2H5) CHzCH=CHzCHaO (EH30 NHCH(CH3)2 CHsO CHaO NHCHzCHzOH CzHsO CgHgO H(CH3)2 CzHsOCzHaO N(C2H5)2 C2H5O 21150 N CH3CH=CH3 2 021150 (3211 0 N N-CH;

CzH5O CzH5O N N-n-propyl (321150 021150 N NCH2-CH=-CH2 CH; CH}; N(CH )13 H: N( 2 s)2 CH CH N-hornopiperidlno CH3 CH3 N(C2H5) CH2CH=CH2 CH3 CH3NHCHzCHgOH CH: CH; N(CHzCHzOH)z H CHQO N(CH:)2 H OHIO N(C2Hs)2 BeriZoN(CHa)z Benzo N( CzHu): BenZo N(CHCH=CH2)2 Benzo N-homoplperidlno BenzoN(CHzCHzOH)2 Benlo N(C2H ).CH2CH=CHg BenZo N N-CHa Benzo N N-n-propylB01120 N N-OH:CH=CH2 BenZD NHCH(OH3)2 Benzo NHCHaCHzOH l l Benzo N NC-EXAMPLE Xi 2-( N ,N-Diethylamino )-6,7-Dimethoxy-4( 3H)-Quinazolinethione A. A mixture of2-(N,N-diethylamino)-6,7-dimethoxy-3,4- dihydroquinaz0line-4-onc g.) asprepared in example lll as its hydrochloride salt in 50 ml. ofphosphorus oxychloride is refluxed for 2 hours, after which, the mixtureis evaporated a]- most to dryness to yield crystalline2-(N,N-diethylamino)-4- chloro-6,I-dimethoxyquinazoline hydrochloride,m.p. l75l 84 C. This product is dissolved in dilute sodium bicarbonatesolution, extracted with chloroform, separated for the dried organicphase evaporated to give the 4-chloro product as the free base in 82%yield, m.p. l29-l 3 1 C.

Anal. Calcd. for c,,H,,0,N,c1. C, 56.86; H, 6.13; N, [4.21;

Found: C, 56.81; H, 6.08; N, 13.97

B. To 7.6 g. of the above obtained intermediate product, 2-(N,N-diethylamino)-4-chlor0-6,7-dimethoxyquinazoline, in I00 ml. oftetrahydrofuran is added a solution of 3.8 g. of sodium hydrogen sulfidehydrate in 30 ml. of water, followed by the addition of 25 ml. of 1NHCl. The resulting solution is stirred for 1 hour at room temperatureand then evaporated to a solid residue which is triturated with l50 ml.of hot chloroform and the insolubles are filtered. The filtrate isconcentrated to a small volume, isopropyl ether added, and the resultingprecipitate is collected. Recrystallization from methanol provided 39 g.(51%) of desired product, m.p. 154-l 57 C.

Anal. Calcd. for C, H, N O S: C, 57.31; H, 6.53; N, 14.32; S, 10.93

Found: C, 57.54; H, 6.52; N, 14.34; S, 11.05

EXAMPLE Xll 2-(N,N-Dimethylamino)-6,7-Dimethoxy-4(3H)-QuinazolinethioneThe procedure of example XI (step A) is repeated wherein astoichiometric equivalent amount of 2-(N,N-dimethylamino)-6,7-dimethoxy-3,4-dihydroquinazolinel-one as prepared bythe method of example IV is used (as its hydrochloride salt) in lieu of2-(N,N-diethylamino)-6,7- dimethoxy-3,4-dihydroquinazoline-4-one andgood yields of 2-(N,N-dimethylamino)-4-chloro-6,7-dimethoxy-3,4-dihydroquinazoline are obtained. This intermediate product is usedfollowing the procedure of example Xl (step B) in place of2-(N,N-diethylamino)-4-chloro-6,7-dimethoxyquinazoline (instoichiometric equivalent amounts) and substantial yield of product isobtained.

EXAMPLE Xlll 2-(N,N-Diallylamino)6,7-Dimethoxy-4( 3H QuinazolinethioneThe procedure of example Xl (step A) is repeated wherein astoichiometric equivalent amount of 2-(N,N-diallylamino)-6,7-diethoxy-3,4-dihydroquinazoline-4-one as prepared by the method ofexample V is used (as its hydrochloride salt) in lieu of2-(N,N-diethylamino )-6,7-dimethoxy-3,4-dihydroquinazoline-4-one andgood yields of 2-(N,N-diallylamino )-4- chloro-6,7-dimethoxyquinazolineare obtained. This intermediate product is used following the procedureof example Xl (step B) in place of Z-(N,N-diethylamino)-4-chloro-6,7-dimethoxyquinazoline in stoichiometric equivalent amounts) andsubstantial yield of product is obtained.

EXAMPLE XIV 2-[N-( N '-Methylpiperazino)]-6,7-Dimethoxy-4(3H)-Quinazolinetbione The procedure of example Xl (step A)is repeated wherein a stoichiometric equivalent amount of2-[N-(N'-methylpiperazino ]-6,7-dimethoxy-3 ,4-dihydroquinazoline-i'oneas prepared by the method of example Vl is used (as its hydrochloridesalt) in lieu of 2-(N,N-diethylamino)-6,7-dimethoxy-3,4-dihydroquinazoline-4-one and good yields of2-[N-(N'-methylpiperazino)]-4-chloro-6,7-dimethoxyquinazoline areobtained. This intermediate product is used following the procedure ofexample Xl (step B) in place of 2-(N,N- diethylamino)-4-chloro-6,7-dimethoxyquinazoline (in stoichiometric equivalentamounts) and substantial yield of product is obtained.

EXAMPLE XV 2-( N-Homopiperidino )-6,7-Dimethoxy-4( 3H)-Quinazolinethione The procedure of example XI (step A) is repeatedwherein a stoichiometric equivalent amount of 2-(N-homopiperidino)-6,7-dimethoxy-3,4'dihydroquinazoline-4-one as prepared by the method ofexample VII is used (as its hydrochloridesalt) in lieu of2-(N,N-diethylamino)-6,'I-dimethoxy-3,4- dihydroquinazoline-4-one andgood yields of 2-(N- homopiperidino)-4-chloro-6,7-dimethoxyquinazolineare obtained. This intermediate product is used following the procedureof example XI (step B) in place of 2-(N,N-diethylamino)-4-chloro-6,7-dimethoxyquinazoline (in stoichiometricequivalent amounts) and substantial yield of product is obtained.

EXAMPLE XVI 2-[N-(N'-n-Propylipiperazino)]-6,7-Dimethoxy-4(3H)-Quinazolinethione The procedure of example XI (step A) is repeatedwherein a stoichiometric equivalent amount of2-[N-(N-n-propylpiperazino)1-6,7-dimethoxy3,4-dihydroquinazoline-4-oneas prepared by the method of example VIII is used (as its hydrochloridesalt) in lieu of 2-(N,N-diethylamino)-6,7-dimethoxy-3,4-dihydroquinazoline-4one and good yields of 2-[N-(N-n-propylpiperazino)]-4-chloro-6,7-dimethoxyquinazoline are obtained.This intermediate product is used following the procedure of example XI(step B) in place of 2-(N,N-diethylamino)-4-chloro-6,7-dimethoxyquinazoline (in stoichiometricequivalent amounts) and substantial yield of product is obtained.

EXAMPLE XVII 2-[N-(N-Allylpiperazino)]-6,7-Dimethoxy-4(3H)Quinazolinethione The procedure of example XI (step A) is repeated wherein astoichiometric equivalent amount of2-[N-(N'-allylpiperazino)]-6,7-dimethoxy-3,4-dihydroquinazoline-4-one asprepared by the method of example IX is used (as its hydrochloride salt)in lieu of 2-(N,N-diethylamino)-6,7-dimethoxy-3,4-dihydroquinazoline-4-one and good yields of2-[N-(N-allylpiperazino)]-4-chloro-6,7-dimethoxyquinazoline areobtained. This intermediate product is used following the procedure ofexample XI (step B) in place of 2-(N,N-diethylamino)-4-chloro-6,7-dimethoxyquinazoline (in stoichiometricequivalent amounts) and substantial yield of product is obtained.

EXAMPLE XVIIA 2-[N-(N'-2-Furoylpiperazino)]-6,7--Dimethoxy-4( 3H)-Quinazolinethione The procedure of example XI (steps A and B) isrepeated wherein 2-[N-(N-2-furoylpiperazino)]-6,7-dimethoxy-3,4-dihydroquinazoline-4-one as prepared by example IXA is used (as itshydrochloride salt) in lieu of 2-(N,N-.diethylamino)-6,7-dimethoxy-3,4-dihydroquinazoline-4-one and substantial yield ofproduct is obtained.

EXAMPLE XVIII The procedure of example XI (steps A and B) is repeated toprepare the quinazolinethiones corresponding to the quinazoline-4-oneslisted in example X wherein the intermediate 4-chloro compounds areisolated and then converted to the desired products. The same molarbasis of reagents is used and good yields are obtained in each instance.

EXAMPLE XIX The hydrochloride salt of 2-(N,N-diethylamino)-.6,7-dimethoxy-3,4-dihydroquinazoline-4-one was prepared by dissolving thecompound in an aqueous solution containing an equivalent amount in molesof hydrochloric acid. Actually, aqueous lN HCl was used for thesepurposes. Upon completion of this step, the resultant solution was thenevaporated to dryness while under reduced pressure to afford the desiredsalt in the form of a crystalline residue. In this manner, there was 10obtained 2-(N,N-diethylamino)-6,7-dimethoxy-3,4-dihydroquinazoline-4-one hydrochloride, m.p. 25025 1 C.

Anal. Calcd. for c u n o HCl: C, 53.59; H, 6.42; N,

13.37 Found: C, 53.73; H, 6.54; N, 13.49

EXAMPLE XX The procedure described in example XIX is repeated to prepareother hydrochlorides, which are listed below in the table together withtheir melting points. In each case, elementary analysis for carbon,hydrogen, nitrogen and chlorine agrees with the calculated values.

2-(N,N-dimethylamino)-6,7-dimethoxy-3,4-dihydroquinazoline-4-onehydrochloride, m.p. 279282 279-C.

2-(N,N-diallylamino)-6,7-dimethoxy-3,4-dihydroquinazoline-4-onehydrochloride, m.p. 233-235 C.

2-( N-homopiperidino)-6,7-dimethoxy-3,4-dihydroquinazoline-4-onehydrochloride, m.p. 244-245 C.

2-[N-(N-methylpiperazino)]-6,7-dimethoxy-3,4- dihydroquinazoline-4-onehydrochloride, m.p. 242-245 C.

EXAMPLE XXI The procedure described in example XIX is repeated toprepare the hydrochloride of 2-(N,N-diethylamino)-6,7-dimethoxy-4(3I-I)-quinazolinethione, m.p. l92-200" C.

EXAMPLE XXII The procedure described in example XIX is repeated toprepare the hydrochlorides of those quinazolinethiones cited in examplesXII, XIII, XIV, XV, XVI, XVIIA and XVI" and substantial yield of productis obtained in each instance.

EXAMPLE XXIII The other acid addition salts of the novel 2-amino-3,4-dihydroquinazoline-4-ones and 2-amino-4( 3 H )-quinazolinethiones ofthis invention, like 2-(N,N-diethylamino)-6,7-dimethoxy-3,4-dihydroquinazoline-4-one hydrobromide, and2-(N,N-diethylamino)-6,7-dimethoxy-4-(3H)-quinazolinethionehydrobromide, are prepared by the same general procedure described inexample XIX, except that in the case of the hydrobromide, hydroiodide,nitrate, sulfate or bisulfate, phosphate or acid phosphate,methanesulfonate, ethanesulfonate, benzenesulfonate andp-toluenesulfonate salts, the corresponding appropriate organic ormineral acid is employed in place of hydrochloric acid, with comparableresults being obtained in each instance.

In like manner, ethanol can be substituted for water in this very sameprocedure with comparable results also being obtained. For instance,when the respective acid and 2-(N,N-diethylamino)-6,7-dimethoxy-3,4-dihydroquinazoline-4-one are bothseparately dissolved in ethanol and the two solutions are then mixed,followed by the addition of diethyl ether to the resulting reactionmixture, there is obtained the desired acid addition salt in the form ofa crystalline precipitate from said solution. This method has also beenused to prepare the corresponding acetate, lactate, citrate or acidcitrate, tartrate or bitartrate, oxalate, benzoate, succinate andmaleate salts of the 2-amino-3,4-dihydroquinazoline-4-one and2-amino-4(3 H)-quinazolinethione compounds of this invention as well.

EXAMPLE XXIV The sodium salt of 2-(N,Ndiethylamino)6,7-dimethoxy-3,4-dihydroquinazoline-4-one and 2-(N,N-diethylamino)-6,7-dimethoxy-4(3I-I)-quinazolinethione are prepared by dissolving thecompound in water, i.e., in an aqueous solution containing a sufficientamount of sodium hydroxide to be equimolar with respect to theamphoteric organic base. Upon freeze-drying of the mixture, the desiredalkali metal salt is obtained.

EXAMPLE xxv EXAMPLE XXVI Other alkali metal and alkaline-earth metalsalts of the novel 2-amino-3,4-dihydroquinazoline-4-ones and Z-amino-4(3H)-quinazolinethiones of this invention are prepared according to thegeneral procedure of the preceding two examples by merely substitutingthe appropriate amphoteric organic base and alkali or alkaline-earthmetal reagent, as the case may be, to obtain the desired results. Forinstance, 2- (N,N-diallylamino)-6,7-dimethoxy-3,4-dihydroquinazoline'4-one and calcium hydroxide react in this manner to afford thecorresponding calcium salt.

In like manner, the corresponding lithium, sodium, potassium, calcium,barium, strontium and magnesium salts of all these compounds are alsoobtained.

EXAMPLE XXVIl The following pharmacological evaluation was carried outto determine the antihypertensive activity of the novel compounds citedbelow in dogs made hypertensive by the procedure of Goldblatt et al. J.Exp. Med. 59, 347 (1934). Doses of 2.5 and 10.0 mgJkg. were administeredorally in capsules on consecutive days in the form of hydrochloridesalts. The systolic pressure was determined on the coccygeal arteryaccording to the method of Prioli and Wenbury, J. App. Physiol. 15, 323(1960), prior to drug administration and 2, 4 and 24 hours thereafter.Heart rates were determined from the simultaneously record ECG. Two dogswere used for evaluation of each compound. An average blood decrease ofless than 10 mm. Hg. was assigned a score of decreases of to 20, to 35and 35 to 60 mm. Hg. were scored -Hl-and *H-h respectively.

Activity at mg. Compound 2.5 10.0

2-(N, N-diethylamlno) -6, 7-dimethoxy-3, 4-dihydroquinazoiinei-one 2-(N,N-dlmethylamino)-6, 7-dimethoxy-3, 4-dihydroquinazolinei-one 0Q-(N-ethyl-N-allylamlno)-6, 7-dimethoxy-3, 4-dihydroqulnazoline-4-one 02-(N, N -diallylarnin0)-6, 7-dimethoxy-3, 4dihydroqulnazollne-4-one 02-[N, N-di(B-hydroxyethy1)amino1-6, 7-dimethoxy-3 4-dihydroquinazoline4-one 0 2-(Nhomoplperldino)-6, 7-dimethoxy-3,4-dihydroqu azoline-t-one 0 2-[N-(N-methylpiperazino)]-G, 7-dimethoxy3,4-dihydroqulnazolinei-one 0 2-(N-monoisopropylamino)-6, 7-dimethoxy-3,-dihydroquinazoline-4-one (l 2-[N-mono(fl-hydroxyethyl)amino]-6,7-dlrnethoxy-3 4-dihydroquinazoline4-one 0 2-(N, N -diethylamino)-6,7-diethoxyfi3, 4 hydroqul zo llne-t-one 2-(N,N-dlmothylamino)-7-methoxy-3, 4-dlhydroqulnazoline-bone Bibi i.- Cwil ned 2-(N, N -dimethyiam.mo

.ollne one" 2-(N, N-diethyl'amino)-6, 7-dunethyl-3, 4-dihydroquinaz- Iollne-4-one .'..;;L.;;;.;;;;;;; 0 1- wherein R, is selected from thegroup consisting of methoxy and ethoxy; R is a member selected from thegroup consisting of N,N-dimethylamino, N,N-diethylamino,N,N-diallylamino, N-homopiperidino, N,N-di (B-hydroxyethyD-amino,N-ethyl- N-allylamino, N,N '-methylpiperazino, N ,N N propyl)piperazino,N,N-allylpiperazino, N- monoisopropylamino, N-mono (B-hydroxyethyDaminoand N,N -2-furoylpiperazino and X is selected from the group consistingof oxygen and sulfur and the slats thereof withpharmacologically-accepted acids and bases.

2. A compound as claimed in claim 1 wherein R, is methoxy, R isN,N-diethylamino and X is oxygen.

3. A compound as claimed in claim 1 wherein R, is methoxy, R isN,N-dimethylamino and X is oxygen.

4. A compound as claimed in claim 1 wherein R, is methoxy, R isN,N-diallylamino and X is oxygen.

5. A compound as claimed in claim 1 wherein R, is methoxy, R isN,N'-methylpiperazino and X is oxygen.

6. A compound as claimed in claim 1 wherein R, is methoxy, R is N,N'-(n-prophyl)piperazino and X is oxygen.

7. A compound as claimed in claim 1 wherein R, is methoxy, R isN,N'-allylpiperazino and X is oxygen.

8. A compound as claimed in claim 1 wherein R, is methoxy, R isN-homopiperidino and X is oxygen.

9. A compound as claimed in claim 1 wherein R, is methoxy, R isN,N'-2-furoylpiperazino and X is oxygen.

10. A compound as claimed in claim 1 wherein R, methoxy, R isN,N-diethylamino and X is sulfur.

11. A compound as claimed in claim 1 wherein R, methoxy, R isN,N-dimethylamino and X is sulfur.

12. A compound as claimed in claim 1 wherein R, methoxy, R isN,N-diallylamino and X is sulfur.

13. A compound as claimed in claim 1 wherein R, methoxy, R isN,N-methylpiperazino and X is sulfur.

14. A compound as claimed in claim 1 wherein R, methoxy, R isN,N'-(n-propyl)piperazino and X is sulfur.

15. A compound as claimed in claim 1 wherein R, methoxy, R isN,N'-allylpiperazino and X is sulfur.

16. A compound as claimed in claim 1 wherein R, methoxy, R isN-homopiperidino and X is sulfur.

17. A compound as claimed in claim 1 wherein R, methoxy, R is N,N-2-furoylpiperazino and X is sulfur.

2. A compound as claimed in claim 1 wherein R1 is methoxy, R isN,N-diethylamino and X is oxygen.
 3. A compound as claimed in claim 1wherein R1 is methoxy, R is N,N-dimethylamino and X is oxygen.
 4. Acompound as claimed in claim 1 wherein R1 is methoxy, R isN,N-diallylamino and X is oxygen.
 5. A compound as claimed in claim 1wherein R1 is methoxy, R is N,N''-methylpiperazino and X is oxygen.
 6. Acompound as claimed in claim 1 wherein R1 is methoxy, R is N,N''-(n-prophyl)piperazino and X is oxygen.
 7. A compound as claimed inclaim 1 wherein R1 is methoxy, R is N,N''-allylpiperazino and X isoxygen.
 8. A compound as claimed in claim 1 wherein R1 is methoxy, R isN-homopiperidino and X is oxygen.
 9. A compound as claimed in claim 1wherein R1 is methoxy, R is N,N''-2-furoylpiperazino and X is oxygen.10. A compound as claimed in claim 1 wherein R1 is methoxy, R isN,N-diethylamino and X is sulfur.
 11. A compound as claimed in claim 1wherein R1 is methoxy, R is N,N-dimethylamino and X is sulfur.
 12. Acompound as claimed in claim 1 wherein R1 is methoxy, R isN,N-diallylamino and X is sulfur.
 13. A compound as claimed in claim 1wherein R1 is methoxy, R is N,N-methylpiperazino and X is sulfur.
 14. Acompound as claimed in claim 1 wherein R1 is methoxy, R is N,N''-(n-propyl)piperazino and X is sulfur.
 15. A compound as claimed inclaim 1 wherein R1 is methoxy, R is N,N''-allylpiperazino and X issulfur.
 16. A compound as claimed in claim 1 wherein R1 is methoxy, R isN-homopiperidino and X is sulfur.
 17. A compound as claimed in claim 1wherein R1 is methoxy, R is N,N''-2-furoylpiperazino and X is sulfur.